tbuckley/cabot-search huggingface dataset:
A phase II prospective trial of MRI and in-bore biopsy in the reclassification of men considering active surveillance for prostate cancer
Authors: B. Langbein, A.P. Cole, B. Berk, M. Labban, K. Tuncali, N. Martin, M. Schostak, F. Fennessy, C. Bay, C. Tempany, A.S. Kibel
Journal: European Urology (2022)
Meta-analysis of randomized phase II-III trials evaluating triplet combinations of immunotherapy and targeted therapy for BRAF V600-mutant unresectable or metastatic melanoma.
Authors: Pier Francesco Ferrucci, Aurora Gaeta, Emilia Cocorocchio, Oriana D'Ecclesiis, Sara Gandini
Journal: Journal of Clinical Oncology (2022)

9541 Background: Immune-checkpoint inhibitors (ICI) and targeted-therapies (TT) have become standard options for BRAF -V600 metastatic melanoma (B-mut MM) patients. However, still more than 50% of those patients do not respond or relapse to these current strategies. Preclinical and translational data suggest that ICI plus TT may improve treatment outcomes in patients with B-mut MM, but with conflicting results in the clinical setting. Methods: We performed a systematic review and meta-analysis of randomized phase II-III studies published until January 2022 comparing first-line ICI+TT vs TT alone in B-mut MM. We obtained summary estimates through random-effects models. Overall survival (OS) and progression-free survival (PFS) were the main outcomes retrieved but we look also at difference in responses and adverse events. Results: We summarized data from 3 independent trials and we showed a significant advantage in terms of PFS and OS for the experimental arms in B-mut MM patients treated with ICI+TT rather than TT alone. The summary estimate indicates a significant 23% decrease in risk of progression (SHR = 0.77, 95%CI: 0.66-0.89, with no between-study heterogeneity I 2 = 0%) and a significant 21% reduction in risk of death (SHR = 0.79, 95%CI: 0.66-0.96, with no heterogeneity I 2 = 0%). However, no difference was shown (p-value = 0.56) between arms in terms of summary Objective Response Rate (ORR) estimates (Summary ORR doublet = 65.4% [61.5%; 69.2%] and Summary ORR triplet = 67% [63%; 70.9%], respectively). From the subgroup analysis on PFS risk estimates, no significant differences were observed in summary HRs by age ( &lt; 65 vs ≥65 years, p-value = 0.11), sex (female vs male, p-value = 0.58), ECOG PS (0 vs 1, p-value = 0.36), LDH levels (lower vs upper, p-value = 0.59) and PDL1 status (positive vs negative, p-value = 0.89). Significant differences were found in frequencies of grade 3 or more adverse events with higher number of events occurring in B-mut MM vs TT alone (Summary Odd Ratio = 2.01, 95%CI: 1.16-3.47, I 2 = 74%), whereas no significant differences were found in terms of any adverse event between arms (SOR = 1.83, 95%CI: 0.70-4.78, I 2 = 0%). Conclusions: This study supports and extend the discussion on first-line available combinations to be offered to B-mut MM patients. Combining ICI with TT demonstrated an effective advantage on both PFS and OS, although augmenting toxicities. Further biomarker-driven investigation may identify patient subpopulations who could benefit from ICI+TT combinations in order to expand their window of therapeutic opportunities.
Editor's Note: Characterization of a Novel Mechanism of Genomic Instability Involving the SEI1/SET/NM23H1 Pathway in Esophageal Cancers
Authors: Yan Li, Chang-Jun Nie, Liang Hu, Yanru Qin, Hai-Bo Liu, Ting-Ting Zeng, Leilei Chen, Li Fu, Wen Deng, Shu-Peng Chen, Wei-Hua Jia, Chunyu Zhang, Dan Xie, Xin-Yuan Guan
Journal: Cancer Research (2022)

The editors are publishing this note to alert readers to a concern about this article (1). We were informed by the authors that the GAPDH Western blot bands in Fig. 3C were mistakenly duplicated from the GAPDH Western blot bands in Fig. 1A.
Upfront FOLFOXIRI plus bevacizumab with or without atezolizumab in the treatment of patients with metastatic colorectal cancer (AtezoTRIBE): a multicentre, open-label, randomised, controlled, phase 2 trial
Authors: Carlotta Antoniotti, Daniele Rossini, Filippo Pietrantonio, Aurélie Catteau, Lisa Salvatore, Sara Lonardi, Isabelle Boquet, Stefano Tamberi, Federica Marmorino, Roberto Moretto, Margherita Ambrosini, Emiliano Tamburini, Giampaolo Tortora, Alessandro Passardi, Francesca Bergamo, Alboukadel Kassambara, Thomas Sbarrato, Federica Morano, Giuliana Ritorto, Beatrice Borelli, Alessandra Boccaccino, Veronica Conca, Mirella Giordano, Clara Ugolini, Jacques Fieschi, Alexia Papadopulos, Clémentine Massoué, Giuseppe Aprile, Lorenzo Antonuzzo, Fabio Gelsomino, Erika Martinelli, Nicoletta Pella, Gianluca Masi, Gabriella Fontanini, Luca Boni, Jérôme Galon, Chiara Cremolini
Journal: The Lancet Oncology (2022)
Lung cancer patients with germline mutations have a unique fusion molecular spectrum.
Authors: Zixin Yang, Likang Zheng, Yaqing Wu, Ningning Luo, Qin Zhang, Xuesong Bu, Tingting Sun, Chuang Qi
Journal: Journal of Clinical Oncology (2022)

e21009 Background: In contrast to numerous studies of somatic mutations, the researches of lung cancer germline mutations remain smaller. Some certain germline mutations are assumed to increase susceptibility to lung cancer. However, the details of such mechanism remain to be established. In this study, DNA profiles were performed by targeted next-generation sequencing (NGS). Methods: A retrospective study of 3,421 lung cancer patients with available NGS data was performed to identify germline mutations. Based on the American College of Medical Genetics and Genomics (ACMG) guidelines, germline mutations were categorized as being pathogenic (P), likely pathogenic (LP) and other significance (Non_P). Thus, the patients were divided into two groups: patients with P or LP mutation(P&amp;LP), and patients with Non_P mutation. Results: Of 3421 patients with lung cancer, 174 (5.09%) patients were identified to carry pathogenic or likely pathogenic germline mutations, with a median age of 62.5 years old. BRCA2, ATM, MUTYH, BRCA1 and ERCC2 were the top five genes with germline alterations, and their mutation rates were 11.5, 6.90, 6.32, 5.17 and 4.60%, respectively. Homozygous mutations were identified in only two patients, one was TP53( p.Ser215Ile), and the other was TSC2(splice site alteration). No statistically significant difference in age and sex between P&amp;LP and Non_P group. Somatic mutation data was also involved in our study. The frequency of gene fusion events was same between these two groups. Interestingly, fusion molecular spectrum of P&amp;LP group was different. Among all the 25 fusion events of P&amp;LP group, 20 were unique and 19 fusion events couldn't be retrieved in the PubMed database. In total, 44 genes involved in fusion events and 5 genes were located on chromosome 17. Frequency of FAT1 single nucleotide variant (SNV) mutation was significantly higher in P&amp;LP group (9.77% vs 5.57%, p = 0.03). Most copy number variations (CNV) were amplification, and frequency of EGFR copy number amplification was higher in P&amp;LP group (19.5% vs 12.6%, p = 0.01). Conclusions: These data implied that genomic profile of lung patients who carried germline gene mutations could be different. Associations between germline mutation and lung cancer susceptibility, treatment will be studied further.
DIPG-06. Uncovering the FACTs in Diffuse Midline Glioma (DMG)
Authors: Holly Holliday, Anahid Ehteda, Aaminah Khan, Brian Krug, Jourdin R C Rouaen, Nisitha Jayatilleke, Chelsea Mayoh, Orazio Vittorio, Nada Jabado, Maria Tsoli, David S Ziegler
Journal: Neuro-Oncology (2022)

Abstract Effective treatments are urgently needed for the incurable paediatric brainstem tumour Diffuse Midline Glioma (DMG). Most DMGs contain Histone H3 mutations (H3K27M), which produce extensive epigenetic dysregulation by inhibiting EZH2-mediated trimethylation of H3K27 (H3K27me3). Global depletion of the repressive H3K27me3 modification results in aberrantly open chromatin and is central to DMG tumorigenesis. Thus, targeting the epigenome is a promising avenue of treatment for DMG. We found that targeting the histone chaperone complex Facilitates Chromatin Transcription (FACT) with the curaxin drug CBL0137 to have potent pre-clinical efficacy against DMG, leading to a paediatric Phase I/II clinical trial for CBL0137 which includes a DMG/DIPG cohort (NCT04870944). In this project we aim to elucidate CBL0137’s molecular mechanism in DMG. FACT is critical for maintaining chromatin homeostasis during DNA replication, transcription, and repair. We therefore hypothesised that FACT maintains the aberrant epigenetic landscape resulting from H3K27M. Consistently, we found CBL0137 to be more cytotoxic against H3K27M-mutant, compared to H3-WT or isogenic DMG cells lacking the mutation. Furthermore, FACT directly interacts with H3K27M, and FACT inhibition increases both EZH2 catalytic activity and global H3K27me3 levels. We are now using ChIP-seq to discover the genome-wide distribution of FACT and H3K27M, and will interrogate the consequence of CBL0137 treatment on the epigenome and transcriptome. Preliminary results suggest that FACT is located at certain genes co-occupied by H3K27M, the active histone mark H3K27ac, and the BET protein BRD4. This implies that FACT is involved in maintaining open chromatin and perhaps transcription at these regions. Combining CBL0137 with other epigenetic drugs, such as BET inhibitors, could therefore represent a rational therapeutic opportunity for DMG. This work will ultimately inform mechanism-based targeted therapies to combine with CBL0137 to improve its efficacy and uncover valuable new insights into DMG epigenetics and pathobiology.
Lymphopenia and outcomes of bendamustine-based therapy in follicular lymphoma.
Authors: Brianna R. Bakow, Arun Muthiah, Adam J Olszewski, James N. Butera
Journal: Journal of Clinical Oncology (2022)

e19540 Background: Bendamustine plus rituximab (BR) is the preferred first-line immunochemotherapy for follicular lymphoma (FL) due to its efficacy and generally favorable adverse effect profile. However, it often causes prolonged lymphopenia, and impaired lymphocyte recovery after BR therapy has been recognized as a risk factor for opportunistic infections. On the other hand, little is known about the impact of profound lymphopenia on the overall treatment outcomes of BR. We examined the relationship between lymphopenia and treatment response in patients with FL who received BR at our institution. Methods: We retrospectively identified patients who received BR as first-line therapy for FL at the Lifespan Cancer Institute between October 2008 and November 2020. We used log-transformed absolute lymphocyte count (ALC) as the potential prognostic variable, integrated as the area under curve based on all available laboratory tests over the typical duration of BR (6 months). Outcomes included complete response to BR determined by post-treatment positron emission tomography or computed tomography, survival, and occurrence of hospitalization or herpes zoster on therapy. The association between ALC and survival or binary endpoints was examined using Cox or logistic models, respectively, adjusting for age, sex, cumulative bendamustine dose, and baseline ECOG performance status (PS). Results: We included 53 patients followed for a median of 69 months from start of BR. At treatment initiation, most patients had a PS of 0-1, stage III or IV disease, and high-risk lymphoma as defined by the Follicular Lymphoma International Prognostic Index (FLIPI) (Table). We observed an association between higher ALC during treatment and increased rates of CR (adjusted odds ratio, 2.50, 95% CI 1.04 – 6.00; p = 0.040), longer progression free survival (PFS) (adjusted hazard ratio [HR], 0.53, 95% CI 0.31 – 0.92, p = 0.023), and overall survival (OS) (HR, 0.45, 95% CI 0.23 – 0.87, p = 0.018). Higher ALC values during treatment and 1 month after treatment initiation were also associated with lower probability of hospitalization (p = 0.048 and p = 0.028, respectively). We did not find a statistically significant association between ALC and rates of zoster infection, but the number of observed events was low (n = 6). Conclusions: Our results suggest an association between higher ALC values during bendamustine therapy and improved treatment outcomes. Improvement in PFS, OS, and hospitalization rates with higher ALC values may be due relative preservation of nutritional balance and immune reserve. The association with survival should be confirmed in larger datasets and its potential mechanism elucidated.[Table: see text]
LGG-43. Reduction in the cerebrospinal fluid protein level after bevacizumab treatment in patients with optic pathway low-grade gliomas
Authors: Natália Dassi, Andrea Cappellano, Marcos Costa, Rodrigo Watanabe, Carolina Soares, Frederico Silva, Daniela Almeida, Patricia Dastoli, Jardel Nicacio, Sérgio Cavalheiro, Nasjla Saba
Journal: Neuro-Oncology (2022)

Abstract Cases Presentations: Case 1: A 1-year-old boy with suprasellar pilocytic astrocytoma with previous history of shunting disfunction, treatment according vinblastine protocol due to anaphylactic reaction with carboplatin presented with ascites and necessity of ventricular-atrial shunt. Due to high protein cerebrospinal fluid (CSF) level (551mg/dl) he was submitted to external ventricular drainage and bevacizumab 10mg/kg was associated to his oncology treatment. After three cycles of bevacizumab, the patients’ CSF protein levels decreased dramatically 178 mg/dL, allowing the shunt procedure without complications and shorter hospital stay. Case 2: A ten-year-old boy with suprasellar pilocytic astrocytoma treated with three lines of chemotherapy showed tumor progression one year after the end of carboplatin-vincristine protocol and shunting disfunction. External ventricular drainage was performed, and the CSF showed 590mg/dl protein level. He was treated with vinblastine 6mg/m2 weekly and bevacizumab 10mg/kg each 14 days. After two cycles of bevacizumab, the protein level was 191mg/dl allowing another V-P shunt procedure. Discussion: Optic pathway gliomas frequently cause elevated cerebrospinal fluid protein concentrations leading to shunts occlusions and failures, necessity of external ventricular drainage and longtime hospitalization, implicating risk of serious infections. Bevacizumab is a monoclonal antibody with immunomodulatory and anti-vascular endothelial growth factor (VEGF) activities that has been used in combination with other chemotherapeutic agents such as irinotecan and vinblastine to treat low-grade gliomas and has been reported to decrease the CSF protein concentration.Final Comments: Bevacizumab treatment in patients with gliomas and high CSF protein levels seems effective in decreasing protein leakage from the vessels to the ventricles, thereby improving the scope for successful shunt placement.
RARE-03. Vision-related quality of life in patients with childhood-onset craniopharyngioma – results of KRANIOPHARYNGEOM 2000 / 2007
Authors: Panjarat Sowithayasakul, Svenja Boekhoff, Carsten Friedrich, Hermann L Müller
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Quality of life (QoL) has become a critical component of therapeutic outcomes in the survivors of childhood-onset adamantinomatous craniopharyngioma (CP) patients. Visual deficiency adversely affects daily functioning and QoL. This study aimed to report the vision-related QoL and associated factors in CP patients. PATIENTS AND METHODS: 120 CP patients recruited between 2001 and 2019 in KRANIOPHARYNGEOM 2000/2007 were included in this study. Mean age at CP diagnosis was 10 years (range: 1.3-16.8 years); age at study was 18 years (range: 6-33 years). The primary outcome measures were QoL assessed by PEDQOL, functional capacity measured by Fertigkeitenskala Münster-Heidelberg ability scale and risk factors associated with decreased QoL during 3 years follow-up in CP patients with and without visual impairment (VI). RESULTS: The most common presenting symptoms were headache (42%), VI (20%), and growth retardation (12%). After diagnosis, VI defined as visual acuity less than 20/40, was found in 87 (70%) patients. Ophthalmologic examination and PEDQOL score were evaluated at three months, one year, and 3 years after CP diagnosis. A difference in the parental assessment of CP patient social functioning within the family was found between patients with and without VI in the first year (48 vs. 39, p=0.017) and third year (43 vs. 37, p=0.011). For the PEDQOL domain autonomy, a difference in self- (51 vs. 45, p=0.029) and parental (47 vs. 42, p=0.048) assessment was observed 3 years after diagnosis. In terms of risk factors, tumor volume more than 21 mm3, incomplete tumor resection and optic atrophy at initial presentation were associated with VI during follow-up. CONCLUSIONS: VI has an impact on QoL after CP. Accordingly, early detection of VI, together with the assessment of the patient’s QoL and the provision of adequate support during follow-up plays an important role in minimizing adverse late effects after CP.
Liquid biopsy for pediatric brain tumor patients: is it prime time yet?
Authors: Liana Nobre, Cynthia Hawkins
Journal: Neuro-Oncology (2022)

Journal Article Liquid biopsy for pediatric brain tumor patients: is it prime time yet? Get access Liana Nobre, Liana Nobre Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, CanadaDivision of Haematology and Oncology, The Hospital for Sick Children, Toronto, Ontario, CanadaInstitute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada Search for other works by this author on: Oxford Academic PubMed Google Scholar Cynthia Hawkins Cynthia Hawkins Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, CanadaDepartment of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, CanadaDivision of Pathology, The Hospital for Sick Children, Toronto, Ontario, Canada Corresponding Author: Cynthia Hawkins, MD, PhD, FRCPC, Division of Pathology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada (cynthia.hawkins@sickkids.ca). Search for other works by this author on: Oxford Academic PubMed Google Scholar Neuro-Oncology, Volume 24, Issue 10, October 2022, Pages 1773–1775, https://doi.org/10.1093/neuonc/noac140 Published: 27 May 2022 Article history Published: 27 May 2022 Corrected and typeset: 17 June 2022
Updated study results of pelcitoclax (APG-1252) in combination with osimertinib in patients (pts) with <i>EGFR</i>-mutant non–small cell lung cancer (NSCLC).
Authors: Li Zhang, Hongyun Zhao, Yanqiu Zhao, Ying Cheng, Jiuwei Cui, Yuxiang Ma, Chen Yang, Jie Zhang, Liang Xu, Juan Yu, Lichuang Men, ZHIYAN LIANG, Dajun Yang, Yifan Zhai
Journal: Journal of Clinical Oncology (2022)

9116 Background: Investigational agent pelcitoclax is a dual BCL-2/BCL-xL inhibitor, which enhanced antitumor effects of osimertinib in preclinical models. A report presented at International Association for the Study of Lung Cancer 2021 World Conference on Lung Cancer demonstrated that the combination of pelcitoclax and osimertinib at the recommended phase 2 dose (RP2D) was safe, and preliminary efficacy was observed in some patients whose disease failed prior osimertinib or other third-generation EGFR-TKI treatments. Here, we further provide safety and efficacy results of this combination therapy. Methods: After RP2D was determined to be pelcitoclax 160 mg per week plus osimertinib 80 mg QD, pts were enrolled into 3 expansion cohorts of 20 pts each: Cohort 1 (EC-1) included those with disease resistant to third-generation EGFR-TKIs; Cohort 2 (EC-2) included those with osimertinib-naïve, EGFR-sensitive or T790M-positive mutations; and Cohort 3 (EC-3) included those with the EGFR exon 20 insertion mutation. Results: At the data cutoff date of January 6, 2022, 61 pts (median age, 56 years [69% female]) had been treated with pelcitoclax plus osimertinib. Among them, 13 were in dose escalation cohorts, 20 in EC-1, 20 in EC-2, and 8 in EC-3. Sixteen pts in EC-2 were EGFR-TKI naïve, and 4 were T790M positive with prior TKI treatment. All pts in EC-2 experienced treatment-related adverse events (TRAEs) but only 4 (20%) had grade ≥ 3. Common TRAEs included increased aspartate aminotransferase (90%) and alanine aminotransferase (85%) levels, reduced platelets (40%), diarrhea (40%), and increased lipase (35%). Among 20 evaluable pts, 17 PRs (85%) were observed and 16 (80%) confirmed. The median (range) time to response was 1.4 (1.2-7.0) months, and the median duration of response (DOR) was not reached. The DOR rate at 9 months after first response was 71.4% (95% CI 25.8-92.0). Seven pts had brain metastases at baseline in EC-2; 2 CRs and 3 PRs were observed intracranially. Conclusions: Osimertinib in combination with targeted therapies has been of clinical interest to improve the outcomes of patients with EGFR-mutant NSCLC. Pelcitoclax plus osimertinib was well tolerated and showed comparable efficacy in TKI-naïve pts. Further randomized control trials are warranted to elucidate the role of pelcitoclax when combined with osimertinib. Clinical trial information: NCT04001777.
Multi-modal single-cell profiling of sarcomas from archival tissue reveals mechanisms of resistance to immune checkpoint inhibitors.
Authors: Blake Caldwell, Sminu Bose, Amit Dipak Amin, Somnath Tagore, Johannes C Melms, Simon Berhe, Matthew Ingham, Gary K. Schwartz, Benjamin Izar
Journal: Journal of Clinical Oncology (2022)

e23518 Background: Single-cell RNA-seq is an enabling technology that may inform the molecular underpinnings of drug response and resistance in patient biopsies. This method is difficult to implement in the study of rare diseases such as sarcomas due to specimen requirements and technical limitations. Methods: Here, we evolved novel methods that we recently reported in melanoma ( Wang, Fan, et al., bioRxiv, 2022), which enable single-nucleus RNA, T cell receptor (snRNA/TCR)-seq, and pool-matched whole-genome sequencing (WGS) from archival, frozen sarcoma tissue. Results: This enabled profiling of 75,716 cells and 788 matched TCR clonotypes from six patients with intimal sarcoma (INS) and undifferentiated pleomorphic sarcomas (UPS), including two matched pair samples from pre/post-immune checkpoint inhibitor (ICI). Our analysis revealed substantial transcriptional cancer cell heterogeneity driven by varying copy number alterations (CNAs). In one patient with INS with a complete response to ICI followed by an isolated recurrence, we identified a rare cancer cell clone defined by CNA (confirmed with WGS) and resulting transcriptional outputs that pre-existed and emerged during resistance. Furthermore, in a patient with UPS with intrinsic resistance to ICI, we find adequate T cell clonal expansion and activation, suggesting appropriate T cell response to ICI dampened by intrinsic mechanisms of ICI resistance within the cancer cells. Non-negative matrix factorization (NMF) analysis identified cell states associated with either intrinsic or adaptive resistance to ICI that was distinct from resistance to doxorubicin. These observations are consistent with those previously reported from sequential biopsies obtained from KEYNOTE-001 in metastatic melanoma ( Wang, Fan, et al., bioRxiv, 2022), which also revealed emergence of pre-existing populations of resistant clones defined by their underlying aneuploidy patterns. Conclusions: Together, these results demonstrate feasibility of implementing single-cell genomics from archival tissue to study sarcoma and propel our understanding of drug resistance. Conceptually, this work suggests that large-scale CNAs may drive cell sub-populations associated with ICI resistance in sarcoma and in other diseases.
Short versus extended treatment with a carbapenem in patients with high-risk fever of unknown origin during neutropenia: a non-inferiority, open-label, multicentre, randomised trial
Authors: Nick A de Jonge, Jonne J Sikkens, Sonja Zweegman, Aart Beeker, Paula Ypma, Alexandra H Herbers, Wies Vasmel, Arne de Kreuk, Juleon L L M Coenen, Birgit Lissenberg-Witte, Mark H H Kramer, Michiel A van Agtmael, Jeroen J W M Janssen
Journal: The Lancet Haematology (2022)